Background and Objectives As we were investigating possible causes of an antigen-specific T cell hyporesponsiveness that we observed in monkeys infected with B. burgdorferi, we noticed that spirochetes induced in vitro the production of IL-10, a well-known anti-inflammatory and immunosuppressive cytokine, in PBMC obtained from normal monkeys. In view of the possible effect that the induction of IL-10 by spirochetes could have on the immune response and in the pathogenesis of Lyme disease, we further investigated this phenomenon. Results Heat-killed B. burgdorferi spirochetes stimulated the in vitro production of IL-10 at both mRNA and protein levels in PBMC of normal rhesus monkeys. A concomitant downmodulation of the IL-2 gene transcription was observed. Neither IL-4 nor IFN- gene expression was ostensibly affected by B. burgdorferi spirochetes. These phenomena were observed regardless of whether the stimulating spirochetes belonged to the B. burgdorferi sensu stricto, B. afzelii, or B. garinii genospecies, the three main species that cause Lyme disease. B. burgdorferi also induced the production of IL-10 in normal human PBMC, indicating that this effect could play a role in human Lyme disease. Purified lipidated OspA but not its unlipidated form induced the production of high levels of IL-10 in normal human PBMC. Thus, the lipid moiety is essential in the induction of IL-10 in normal cells. B. burgdorferi strain M297, a mutant strain that lacks the plasmid that encodes OspA and OspB also induced the IL-10 gene transcription in normal cells, indicating that this phenomenon is not causally linked exclusively to OspA. Future Direction To determine the role that IL-10 could play in vivo in both the avoidance by the spirochete of deleterious immune responses as well as in limiting the inflammation that the spirochete is able to induce.